Obesity is a major public health problem that has reached epidemic proportions. Genetics is a major determinant of obesity, however, little is known about specific genes that contribute to obesity. This project addresses that problem by searching for genes in regions that have shown significant linkage to body mass index (BMI), a widely used measure of obesity, in the Framingham Heart Study (FHS). Preliminary analyses have shown that three regions on chromosome 6, 10, and 11 are significantly linked to BMI. The maximum lod scores in these three regions were 4.64, 4.23 and 5.41, respectively. Furthermore, analysis of the longitudinal data available over 28 years in families showed that the linkage signals on all three chromosomes show evidence of being age-dependent. This analysis is one of the first to show age dependent locus effects. This project will locate a gene that affect BMI in one of these three linked regions by proceeding as follows. First, additional highly polymorphic markers will be genotyped in the three regions to improve genetic information. Then, linkage analysis, along with a new method called resampling linkage analysis will be performed in the regions. These analytical approaches will significantly reduce the size of the linked region on all three chromosomes. The single region that gives the best chance of finding the BMI gene will be chosen for further study. In that region we will chose 30 candidate genes for association analysis. Approximately 15 single nucleotide polymorphisms (SNPs) will be genotyped in each of the candidate genes. Fifteen SNPs should yield complete linkage disequilibrium coverage of each candidate gene. Association analysis will then be performed to detect any relationship of this gene with BMI. Finally, the most significant SNPs will be genotyped in an unrelated sample of FHS participants and in the third generation of Framingham participants. Association tests will be repeated to independently confirm that polymorphisms in this gene have an effect on BMI. [unreadable] [unreadable]